PTTG and PBF Functionally Interact with p53 and Predict Overall Survival in Head and Neck Cancer

Abstract

Head and neck squamous cell carcinoma (HNSCC) is the 6th most common cancer worldwide and poses a significant health burden due to its rising incidence. Although the proto-oncogene pituitary tumor-transforming gene 1 (PTTG) predicts poor patient outcome, its mechanisms of action are incompletely understood. We show here that the protein PBF modulates PTTG function, is overexpressed in HNSCC tumors, and correlates with significantly reduced survival. Lentiviral shRNA attenuation of PTTG or PBF expression in HNSCC cells with either wild-type or mutant p53, and with and without HPV infection, led to dysregulated expression of p53 target genes involved in DNA repair and apoptosis. Mechanistically, PTTG and PBF affected each other's interaction with p53 and cooperated to reduce p53 protein stability in HNSCC cells independently of HPV. Depletion of either PTTG or PBF significantly repressed cellular migration and invasion and impaired colony formation in HNSCC cells, implicating both proto-oncogenes in basic mechanisms of tumorigenesis. Patients with HNSCC with high tumoral PBF and PTTG had the poorest overall survival, which reflects a marked impairment of p53-dependent signaling. These findings reveal a complex and novel interrelationship between the expression and function of PTTG, PBF, and p53 in human HNSCC that significantly influences patient outcome. .

The Oncogenic Roles of PTTG1 and PTTG2 Genes and Pseudogene PTTG3P in Head and Neck Squamous Cell Carcinomas

“…These findings indicate that higher expression of PTTG3P, PTTG1 and PTTG2 is connected with activation of prosurvival and protumorigenic downstream genes by mutant p53 protein. Indeed, our observations are supported by the results obtained by Read et al; however, their analysis focused solely on PTTG1 [ 34 ]. In our work, we separately examined the roles of PTTG3P , PTTG1 and PTTG2.…”

“…TCGA data analysis of breast cancer patients performed by Lou et al showed a positive correlation between the PTTG3P pseudogene and TP53 signaling pathways [ 33 ]. Moreover, Read et al reported that PTTG1 and PBF ( PTTG1IP , PTTG1 interacting protein) together modulate the interaction with TP53, reduce p53 protein stability and affect its downstream targets which lead to worse outcomes in HNSCC patients [ 34 ]. Our results indicated that expression levels of PTTG3P , PTTG1 and PTTG2 depend on TP53 mutation type.…”

“…Read et al indicated that PTTG1 together with PTTG1IP play an important role in regulation of p53 protein stability [ 34 ]. We observed correlation between all PTTG3P, PTTG1 and PTTG2 in HNSCC patients.…”

“…High expression of PTTG1 was found to be associated with advanced cancers and short disease-free survival. Moreover Read et al, postulated that PTTG1IP does not reduce the stability of mutated p53 as it is observed in the case of mutant p53 protein in colorectal tumors [ 34 ]. The transcripts of PTTG3P , PTTG1 and PTTG2 seem to complement each other in fulfilling their biological function and influence on cellular program.…”

miR-93-5p enhances migration and invasion by targeting RGMB in squamous cell carcinoma of the head and neck

“…Squamous cell carcinoma of the head and neck (SCCHN) is the sixth most common tumor worldwide, with approximately 650,000 cases being reported annually over the past few decades [1,2]. Despite advances in therapeutic strategies, the 5-year survival rate for SCCHN has not significantly improved, and this lack of improvement is due to late diagnosis, frequent loco-regional recurrences at the primary site, and cervical lymph node metastasis [3,4].…”